About 10 percent of American families are affected by infertilily. Among which, one-third 01 these cases are due to female factOfs, one third to male factOfs, and the remainder are a mixture or have unknown causes. Mitochondrial dysfunction is responsible fOf a wide variety of severe mitochondrial diseases. Impairment of mitoc:hondrial function is one of the factors thaI contribute to infertility. In addition, it is associa ted with a series of other human diseases and conditions, including atherosclerosis and cardiovascular disease. insulin resistance, age-related neurodegenerative diseases, human ageing, and infertjljty. Mammalian models with defined mitochondrial dysfunction suitable fOf reproductive disease studies are nOI available at present. We recently generated a mouse mutant, Jmmp2l"T~JD7P<Mllmmp2IT~~leo.., with deficiency in the mitochondrial inner membrane peptidase IMMP2L. The mutation impairs the signal peptide cleavage of cytochrome cl and affects the mitochondrial function such that the mutants develop normally but show male and female infertility. Al though the main mechanism for the infertility of mutant males is erectile dysfunction, mutant males develop an age-dependent spermatogenic defects which is most likely caused by increased germ cell apoptosis. Thus this mutant holds great potential as a valuable model foc the study of elevated mitochondrial superoxlde generation in human spermatogenesis. Two specific aims are proposed to study the effects of mitochondrial superoxide overgeneration on spermatogenesis. Aim 1 is to determine the damages caused by elevated superoxide generation on germ cells of older mutant males. Aim 2 is 10 study tile effects of mitochondrial dysfunction on germ cell apoptosis. Together, experiments proposed in this application will answer questions such as how elevated mitochondrial superoxide generation can damage male germ cells, impair spermatogenesis, and trigger germ cell apoptosis. Data obtained from this project wiU improve our understanding of the effects of mitochondrial dysfunction on male reproductive and benefit the developing of new treatments for male infertilily.